Disruption of Critical Period Plasticity in a Mouse Model of Neurofibromatosis Type 1

Abstract

Neurofibromatosis type 1 (NF1) is a common monogenic neurodevelopmental disorder associated with physical and cognitive problems. The cognitive issues are thought to arise from increased release of the neurotransmitter γ-amino butyric acid (GABA). Modulating the signaling pathways causing increased GABA release in a mouse model of NF1 reverts deficits in hippocampal learning. However, clinical trials based on these approaches have so far been unsuccessful. We therefore used a combination of slice electrophysiology, in vivo two-photon calcium imaging and optical imaging of intrinsic signal in a mouse model of NF1 to investigate whether cortical development is affected in NF1, possibly causing lifelong consequences that cannot be rescued by reducing inhibition later in life. We find that in NF1 mice of both sexes, inhibition increases strongly during the development of the visual cortex and remains high. While this increase in cortical inhibition does not affect spontaneous cortical activity patterns during early cortical development, the critical period for ocular dominance plasticity is shortened in NF1 mice due to its early closure but unaltered onset. Notably, after environmental enrichment, differences in inhibitory innervation and ocular dominance plasticity between NF1 mice and wildtype litter mates disappear. These results provide the first evidence for critical period dysregulation in NF1 and suggest that treatments aimed at normalizing levels of inhibition will need to start at early stages of development. Significance: Neurofibromatosis type 1 is associated with cognitive problems for which no treatment is currently available. This study shows that in a mouse model of Neurofibromatosis type 1, cortical inhibition is increased during development and critical period regulation is disturbed. Rearing the mice in an environment that stimulates cognitive function overcomes these deficits. These results uncover critical period dysregulation as a novel mechanism in the pathogenesis of Neurofibromatosis type 1. This suggests that targeting the affected signaling pathways in Neurofibromatosis type 1 for the treatment of cognitive disabilities may have to start at a much younger age than has so far been tested in clinical trials.

Developmentally regulated impairment of parvalbumin interneuron synaptic transmission in an experimental model of Dravet syndrome

“…We performed immunohistochemical labeling (see STAR Methods ) for synaptotagmin-2 (Syt2), a specific marker of PV-IN synapses ( Sommeijer and Levelt, 2012 ; Bouhours et al, 2017 ; van Lier et al, 2020 ), and confirmed that Syt2-positive boutons were perisomatic and PV positive ( Figure S8A ). We then quantified the number of PV-IN boutons surrounding the cell bodies of PCs in all experimental groups ( Figure S8B ) and found a small but statistically significant decrease in the number of Syt2-positive puncta around PCs in Scn1a +/− P16–P21 SUDEP relative to Scn1a +/− P16–P21 SURVIVOR and WT P16–P21 and in Scn1a +/− P35–P56 relative to WT P35–P56 ( Figure S8C ).…”

A new era for myelin research in Neurofibromatosis type 1

“…Furthermore, myelin‐based treatments in adults are envisioned. The current view that neurological issues in developmental/genetic diseases are unavoidable and permanent is supported by developmental processes occurring within an established window of time in NF1 (van Lier et al, 2020; Wang, Kim, et al, 2012), which can limit therapeutic windows. Nonetheless, experimental evidence from several groups contrast this view and envision successful treatments in postnatal‐adult patients (Barco et al, 2006; Costa et al, 2002; Cui et al, 2008; Ho et al, 2007; Lee et al, 2014; Li et al, 2005; López‐Juárez et al, 2017; Pagani et al, 2009; Thomas & Huganir, 2004; Viosca et al, 2009).…”

Visual Cortical Plasticity: Molecular Mechanisms as Revealed by Induction Paradigms in Rodents

“…Plasticity defects may be seen in conditions marked by impaired neurodevelopment. In a mouse model of neurofibromatosis type 1, a model to study ASD, high levels of inhibition were observed in the adult V1, with no overt effects on early cortical development [73]. The authors found increased inhibition during development to be the cause of early closure of the CP for OD plasticity.…”